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Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals Myrocin G as an Inhibitor of the Nonhomologous End Joining DNA Repair Pathway

  • Daniel Abegg
    Daniel Abegg
    Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
    More by Daniel Abegg
  • Martin Tomanik
    Martin Tomanik
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
  • Nan Qiu
    Nan Qiu
    Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
    More by Nan Qiu
  • Dany Pechalrieu
    Dany Pechalrieu
    Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
  • Anton Shuster
    Anton Shuster
    Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
  • Bruno Commare
    Bruno Commare
    Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093 Zürich, Switzerland
  • Antonio Togni
    Antonio Togni
    Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093 Zürich, Switzerland
  • Seth B. Herzon
    Seth B. Herzon
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
    Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, United States
  • , and 
  • Alexander Adibekian*
    Alexander Adibekian
    Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
    *Email [email protected]
Cite this: J. Am. Chem. Soc. 2021, 143, 48, 20332–20342
Publication Date (Web):November 24, 2021
https://doi.org/10.1021/jacs.1c09724
Copyright © 2021 American Chemical Society

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    Abstract

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    Chemoproteomic profiling of cysteines has emerged as a powerful method for screening the proteome-wide targets of cysteine-reactive fragments, drugs, and natural products. Herein, we report the development and an in-depth evaluation of a tetrafluoroalkyl benziodoxole (TFBX) as a cysteine-selective chemoproteomic probe. We show that this probe features numerous key improvements compared to the traditionally used cysteine-reactive probes, including a superior target occupancy, faster labeling kinetics, and broader proteomic coverage, thus enabling profiling of cysteines directly in live cells. In addition, the fluorine “signature” of probe 7 constitutes an additional advantage resulting in a more confident adduct–amino acid site assignment in mass-spectrometry-based identification workflows. We demonstrate the utility of our new probe for proteome-wide target profiling by identifying the cellular targets of (−)-myrocin G, an antiproliferative fungal natural product with a to-date unknown mechanism of action. We show that this natural product and a simplified analogue target the X-ray repair cross-complementing protein 5 (XRCC5), an ATP-dependent DNA helicase that primes DNA repair machinery for nonhomologous end joining (NHEJ) upon DNA double-strand breaks, making them the first reported inhibitors of this biomedically highly important protein. We further demonstrate that myrocins disrupt the interaction of XRCC5 with DNA leading to sensitization of cancer cells to the chemotherapeutic agent etoposide as well as UV-light-induced DNA damage. Altogether, our next-generation cysteine-reactive probe enables broader and deeper profiling of the cysteinome, rendering it a highly attractive tool for elucidation of targets of electrophilic small molecules.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c09724.

    • Complete experimental details and procedures, supporting figures, proteomics tables, and NMR spectra (PDF)

    • Tables S1−S12 (XLSX)

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    Cited By

    This article is cited by 9 publications.

    1. Ian Tingyung Hsu, Seth B. Herzon. Fragment Coupling Approach to Diaporthein B. The Journal of Organic Chemistry 2023, 88 (4) , 2221-2244. https://doi.org/10.1021/acs.joc.2c02655
    2. Minervo Perez, Kellie D. Nance, Daniel W. Bak, Supuni Thalalla Gamage, Susana S. Najera, Amy N. Conte, W. Marston Linehan, Eranthie Weerapana, Jordan L. Meier. Conditional Covalent Lethality Driven by Oncometabolite Accumulation. ACS Chemical Biology 2022, 17 (10) , 2789-2800. https://doi.org/10.1021/acschembio.2c00384
    3. Li Xue, Dehao Yu, Lingling Wang, Jing Sun, Ying Song, Yuanyuan Jia, Ang Wu, Beibei Zhang, Wenyi Mi, Heli Fan, Huabing Sun. Selective Antitumor Activity and Photocytotoxicity of Glutathione-Activated Abasic Site Trapping Agents. ACS Chemical Biology 2022, 17 (4) , 797-803. https://doi.org/10.1021/acschembio.2c00061
    4. Franco F. Faucher, Daniel Abegg, Phillip Ipock, Alexander Adibekian, Scott Lovell, Matthew Bogyo. Solid Phase Synthesis of Fluorosulfate Containing Macrocycles for Chemoproteomic Workflows. Israel Journal of Chemistry 2023, 5 https://doi.org/10.1002/ijch.202300020
    5. Minqi Zhou, Zhang Feng, Xingang Zhang. Recent advances in the synthesis of fluorinated amino acids and peptides. Chemical Communications 2023, 59 (11) , 1434-1448. https://doi.org/10.1039/D2CC06787K
    6. Fa‐Jie Chen, Jianmin Gao. Fast Cysteine Bioconjugation Chemistry. Chemistry – A European Journal 2022, 28 (66) https://doi.org/10.1002/chem.202201843
    7. Junying Zhou, Ningjing Lei, Wanjia Tian, Ruixia Guo, Mengyu Chen, Luojie Qiu, Fengling Wu, Yong Li, Lei Chang. Recent progress of the tumor microenvironmental metabolism in cervical cancer radioresistance. Frontiers in Oncology 2022, 12 https://doi.org/10.3389/fonc.2022.999643
    8. Esben B. Svenningsen, Rasmus N. Ottosen, Katrine H. Jørgensen, Marija Nisavic, Camilla K. Larsen, Bente K. Hansen, Yong Wang, Kresten Lindorff-Larsen, Thomas Tørring, Stephan M. Hacker, Johan Palmfeldt, Thomas B. Poulsen. The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21. RSC Chemical Biology 2022, 3 (10) , 1216-1229. https://doi.org/10.1039/D2CB00161F
    9. Mei-Hua Shen, Yu-Jiao Wang, Yong Wang, Ying Zhou, Jie Gu, Xiao-Qian Liu, Jia Guo, Mingxing Ouyang, Linhong Deng, Hua-Dong Xu. α-Vinyl azide–cysteine click coupling reaction enabled bioorthogonal peptide/protein modification. Organic Chemistry Frontiers 2022, 9 (17) , 4654-4662. https://doi.org/10.1039/D2QO00736C

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